Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease that primarily affects the skin and is characterized by hardening (sclerosis) of the skin and internal organs due to the excessive accumulation of collagen. Further, scleroderma is characterized by damage to small blood vessels, activation of T lymphocytes and production of antinuclear antibodies.
Limited scleroderma involves cutaneous manifestations that mainly affect the hands, arms and face, with the following common manifestations: calcinosis (deposition of calcium nodules in the skin), Raynaud's phenomenon (exaggerated vasoconstriction in the hands, with fingers undergoing white-blue-red color transitions in the cold), esophageal dysfunction (leading to difficulty swallowing), sclerodactyly (skin thickening on the fingers), and telangiectasias (dilated capillaries on the face, hands and mucous membranes) with internal organ involvement many years after disease diagnosis. On the other hand, diffuse scleroderma progresses rapidly and is quite disabling, affecting a large area of the skin and internal organs, such as the kidneys, esophagus, heart and/or lungs.
The prognosis is dire for limited cutaneous scleroderma patients who escape pulmonary complications (they generally die of lung failure within 30 years post diagnosis), but is even worse for those with the diffuse cutaneous disease, particularly in patients who are older and/or male. Death occurs most often from pulmonary, heart and kidney complications. In diffuse cutaneous disease, five-year survival is about 70% and 10-year survival is about 55%.
Scleroderma is of unknown etiology, but is often thought to be an autoimmune condition. Further, strong associations between scleroderma and certain mutations in the human leukocyte antigen (HLA) gene and/or environmental factors have been identified.
There are no approved treatments or cures for scleroderma itself, but individual organ system complications may be treated. Systemic disease-modifying treatment with immunosuppressants is often used in scleroderma. Immunosuppressants used include azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, intravenous immunoglobulin, rituximab, sirolimus, alefacept, and the tyrosine kinase inhibitors, imatinib, nilotinib and dasatinib. Experimental therapies currently under investigation include endothelin receptor antagonists, tyrosine kinase inhibitors, beta-glycan peptides, halofuginone, basiliximab, alemtuzumab, abatacept and hematopoietic stem cell transplantation.
Anakinra (KINERET®) and rilonacept (ARCALYST®) are currently undergoing clinical trials for the treatment of scleroderma. These drugs, which are large recombinant proteins requiring direct infusions, directly target interleukin 1 (IL-1) signaling by either interfering with the IL-1 receptor (IL-1R) or sequestering IL-1 from the circulation. Anakinra is a human IL-1R antagonist, binding to IL-1R and blocking its binding of IL-1α or IL-1β. Rilonacept is a dimeric protein comprising the ligand-binding domains of the extracellular portions of the human IL-1R and human IL-1R accessory protein linked to the Fc portion of human immunoglobulin G1 (IgG1). Rilonacept binds and neutralizes circulating IL-1. Anakinra and rilonacept are also used in treating other autoimmune diseases such as rheumatoid arthritis, lupus, and Sjogren's syndrome.
Currently there is a critical lack of approved therapies for IL-1R-mediated diseases or disorders, such as the orphan disease scleroderma. There is thus a need in the art for novel therapeutic compounds that treat or ameliorate scleroderma, or a complication or symptom thereof, in mammals. The present invention fulfills this need.